§1.1 Field of the Invention
This invention relates generally to the field of sensors and in particular to biosensors specific to nucleotide sequences.
§1.2 Background Information
Diagnostics for DNA sequence variations have increasing importance for revealing genetic markers in the exploration of diseases and traits with complex inheritance patterns and strong environmental interactions.
The use of potentiometric ion electrodes (ISEs) represents one of the oldest classes of chemical sensors. The selectivities of these potentiometric ion sensors were quantitatively related to equilibria at the interface between the sample and the electrode membrane by Bakker et al. (See, e.g., Eric Bakker, Emo Pretsch, Philippe Buhlmann, Anal. Chem. 2000 72 1127-1133.)
Melnikov, Sergeyev and Yoshikawa applied a potentiometric study of the binding equilibrium of cationic surfactants with DNA. The calibration curve consisted of the titration curve with the surfactants and the experiment itself followed the addition of DNA to the surfactant solution. The deviation from the calibration was believed to be due to the decrease in the free surfactant concentration caused by the binding to the oppositely charged DNA macro-ions. (See, e.g., S. M. Melnikov, V. G. Sergeyev, K. Yoshikawa, “Transition of Double-Stranded DNA Chains between Random Coil and Compact Globule States Induced by Cooperative Binding of Cationic Surfactant,” JACS, 1995, 117, 9951-9956.)
McConnell et. al. used a silicon-based device (a microphysiometer) to measure the rate of protein excretion from cells during binding of ligands for specific membrane receptors. Because of the use of specific ligands, microphysiometer measures selectively the acidic products of energy metabolism or other physiological changes from changes in intracellular pH. (See, e.g., H. M. McConnell, J. C. Owicki, J. W. Parce, D. L. Miller, G. T. Baxter, H. G. Wada, S. Pitchford Science 1992 257 1906-1912.)
The potentiality of such an ion sensitive detection lies in the development of ion sensitive field effect transistors and especially using binding on surfaces of nanoscale elements such as single wall carbon nano tubes, because the binding can lead to changes in the number of carriers in the nanometer diameter structure (and not only in the surface conductivity as in planar devices) and thus increase the sensitivity to single-molecule level. (See, e.g., Y. Cui, Q. Wei, H. Park, C. M. Lieber, Science 2001 293.)
It would be useful to have an improved sensor and sensing method and system for detecting the presence and/or concentration of nucleotide strands. It would be useful if such a sensor and sensing method and system did not require the application of a voltage from an external source.